Rhein and Diacerhein Compounds
Rhein or diacerhein compounds have been described in a large number of publications and patents (Carney, 1996; Pelletier et al., 2000; Spencer et al., 1997; Smith et al., 1999; U.S. Pat. No. 4,950,687; U.S. Pat. No. 4,244,968; U.S. Pat. No. 5,986,129; U.S. Pat. No. 5,652,265; U.S. Pat. No. 6,124,358; European Patent No. 0809995; U.S. Pat. No. 4,346,103; U.S. Pat. No. 4,950,687). Although rhein is the bioactive compound, diacerhein, the acetylated derivative of rhein, enhances bioavailability and has been deemed the drug of choice.
Anti-Arthritic Activity
Rhein or diacerhein compounds are known for their anti-arthritic activity, and have been used clinically for the treatment of osteoarthritis, a degenerative disease resulting in articular cartilage loss with aging. The dosage of treatment is approximately 25 to 200 mg daily, either administered as a single dose or divided into 2 to 4 courses daily. Patients treated have shown marked improvements in the clinical signs of osteoarthritis. There are no significant toxicities associated with rhein or diacerhein compounds, with the exception of a laxative effect found in a significant proportion of patients treated. Most research associated with rhein or diacerhein compounds has focused on attempting to alter administration or formulation to increase absorption and bioavailability, in an attempt to reduce this side effect.
Several studies have investigated the effects of diacerhein on animal models for osteoarthritis, and have consistently demonstrated cartilage protection. These studies used diacerhein dosages ranging around 5 to 50 mg/kg for periods as long as 50 weeks and found that the treatment reduced the severity of osteoarthritis (Carney, 1996; Tamura et al., 1999; Moore et al., 1998).
A large number of in vitro studies using synoviocyte cultures, cartilage explant cultures or chondrocyte cultures or other similar systems have shown that diacerhein may alter the action of interleukin-1 activating enzymes such as ICE, nitric oxide synthesis, TGF-beta synthesis and matrix synthesis (Moldovan et al., 2000; Felisaz et al., 1999; Pujol et al., 2000). Diacerhein stimulates prostaglandin E2 synthesis, an effect not seen in non-steroidal inflammatory agents that are commonly used for the treatment of osteoarthritis and inflammatory diseases. Inhibition of prostaglandin E2 is thought to be necessary for the inhibition of inflammation. Accordingly, diacerhein has been primarily used to treat degenerative diseases such as osteoarthritis rather than inflammatory diseases such as rheumatoid arthritis, wherein diacerhein would be thought to provide the opposite of the intended effect.
Vascular Diseases That Cause Obstruction of the Vascular System
Diacerhein inhibits iron regulatory protein activation in inflamed human monocytes, alters lymphocyte membrane fluidity and alters macrophage activity and neutrophil phagocytosis (Pietrangelo et al., 1998). However, there is no compelling evidence that rhein or diacerhein compounds play a role in treatment of diseases other than osteoarthritis. Specifically absent is any information indicating that rhein or diacerhein compounds play a role in vascular diseases that cause obstruction of the vascular system.
Blood vessel stenosis is a vascular disease that causes obstruction of the vascular system; it may be caused by intimal hyperplasia resulting in atherosclerosis; it may also occur following vascular or coronary interventions.
Blood Vessel Restenosis
Vascular and coronary surgical interventions have become fairly commonplace as methods of treatment of heart disease or diseases of the vasculature. Such interventions include coronary artery bypass surgery, saphenous-vein bypass grafting, perivascular grafting, carotid endarterectomy, reconstructive surgery of arteries that supply lower extremities, heart transplantations, balloon angioplasty, local balloon delivery, endovascular stenting, intravascular stenting, atherectomy or laser ablation carotid endarterectomy, and hemodialysis grafts.
Of these interventions, balloon angioplasty and coronary stents have become some of the most widely used treatments for heart diseases and diseases of the vasculature (such as coronary artery disease). According to the American College of Cardiology, more than 700,000 coronary stent procedures are performed annually in the U.S. When treating coronary artery disease with balloon angioplasty or coronary stents, an ongoing problem has been the high incience of blood vessel restenosis, a recurrence of coronary artery blockage at the site of treatment. Although balloon angioplasty is an effective treatment to open narrowed or blocked coronary arteries, restenosis occur in about 20–50% of cases within 6 months (Garas et al., 2001). Coronary stents, originally seen as a partial solution to the restenosis that occurs with balloon angioplasty, suffer from the same problem, with the major remaining limitation of coronary stenting being that said stents can also become narrowed through restenosis in the first 6 months post-treatment by ingrown tissue growing through the coronary stents.
It has been postulated for several years that applying small amounts of radiation to the area of coronary artery being treated might prevent restenosis. Recently, the first coronary artery radiation system (the Beta-Cath system of Novostre Corp.) has been approved and the use of the system is limited to restenosis occurring in coronary stents. However, there are problems associated with this type of therapy that may lead to more complications over time. For instance, patients who receive intra-coronary radiation appear to have an increased incidence of late coronary artery stenosis. In addition, there have also been observations of appearance of restenosis of the coronary artery at the edges of the radiation field after treatment (French et al., 2002, Williams, 2002). The FDA has urged the long-term monitoring of patients receiving intra-coronary radiation.
To date, the most promising method of preventing restenosis appears to be in the form of drug-eluting coronary stents. A drug-eluting coronary stent is coated with a drug using a coating technology designed to control the release of said drug into the surrounding tissue. The intention of this time-release process is to slow down the growth of unwanted cells (restenosis) and allow the vessel to heal. Currently, there are several drug-coated stents either in early clinical trials or that have been recently approved; these include rapamycin, paclitaxel and actinomycin-D coated stents. However, recent clinical findings have revealed disappointing results for some of the drug-eluting stent studies. In the paclitaxel derivative-eluting stent study, restenosis rate increased to greater than 60% after a 12-month follow up (Liistro et al., 2002). Guidant has also recently halted further clinical development of actinomycin-D eluting stents because clinical trials revealed the ineffectiveness of actinomycin D in preventing restenosis. Patients treated with actinomycin-D eluting stents have an unacceptably high target lesion revascularization rate (Guidant website, Mar. 7, 2002).
Atherosclerosis
Cardiovascular disease is a serious problem and accounts for 44% of the mortality in the USA. Atherosclerotic cardiovascular disease is a generalized process that involves the brain, heart, and peripheral arteries. Atherosclerosis is characterized by intimal thickening caused by the accumulation of cells, infiltration of inflammatory cells, lipids and connective tissues that can lead to cardiac and cerebral infarction (such as heart attack and stroke). Atherosclerosis is characterized by occlusion of an artery, leading to a series of clinical complications such as myocardial infarction and stroke. Prevention of the occlusion of the artery, by preventing the migration of cells to said artery or by preventing the proliferation of cells within the cell wall of said artery, will result in the prevention or treatment of this disease thereby reducing the incidences of clinical complications arising from this disease.
Needs
Accordingly, there is a need for the development of superior treatments for vascular diseases that cause obstruction of the vascular system such as blood vessel restenosis following vascular and coronary intervention and atherosclerosis.
In summary, there is no published information indicating that rhein or diacerhein compounds play a role in the treatment or prevention of vascular diseases that cause obstruction of the vascular system such as blood vessel restenosis and atherosclerosis.